Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

Holger Hengel; Shabab B Hannan; Sarah Dyack; Sara B MacKay; Ulrich Schatz; Martin Fleger; Andreas Kurringer; Ghassan Balousha; Zaid Ghanim; Fowzan S Alkuraya; Hamad Alzaidan; Hessa S Alsaif; Tadahiro Mitani; Sevcan Bozdogan; Davut Pehlivan; James R Lupski; Joseph J Gleeson; Mohammadreza Dehghani; Mohammad Y V Mehrjardi; Elliott H Sherr; Kendall C Parks; Emanuela Argilli; Amber Begtrup; Hamid Galehdari; Osama Balousha; Gholamreza Shariati; Neda Mazaheri; Reza A Malamiri; Alistair T Pagnamenta; Helen Kingston; Siddharth Banka; Adam Jackson; Mathew Osmond; Care4Rare Canada Consortium; Genomics England Research Consortium; Angelika Rieß; Tobias B Haack; Thomas Nägele; Stefanie Schuster; Stefan Hauser; Jakob Admard; Nicolas Casadei; Ana Velic; Boris Macek; Stephan Ossowski; Henry Houlden; Reza Maroofian; Ludger Schöls

doi:10.1016/j.ajhg.2021.04.024

Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

Am J Hum Genet. 2021 Jun 3;108(6):1069-1082. doi: 10.1016/j.ajhg.2021.04.024. Epub 2021 May 21.

Authors

Holger Hengel¹, Shabab B Hannan¹, Sarah Dyack², Sara B MacKay³, Ulrich Schatz⁴, Martin Fleger⁵, Andreas Kurringer⁵, Ghassan Balousha⁶, Zaid Ghanim⁷, Fowzan S Alkuraya⁸, Hamad Alzaidan⁹, Hessa S Alsaif¹⁰, Tadahiro Mitani¹¹, Sevcan Bozdogan¹², Davut Pehlivan¹³, James R Lupski¹⁴, Joseph J Gleeson¹⁵, Mohammadreza Dehghani¹⁶, Mohammad Y V Mehrjardi¹⁷, Elliott H Sherr¹⁸, Kendall C Parks¹⁸, Emanuela Argilli¹⁸, Amber Begtrup¹⁹, Hamid Galehdari²⁰, Osama Balousha²¹, Gholamreza Shariati²², Neda Mazaheri²⁰, Reza A Malamiri²³, Alistair T Pagnamenta²⁴, Helen Kingston²⁵, Siddharth Banka²⁶, Adam Jackson²⁷, Mathew Osmond²⁸; Care4Rare Canada Consortium²⁸; Genomics England Research Consortium²⁹; Angelika Rieß³⁰, Tobias B Haack³⁰, Thomas Nägele³¹, Stefanie Schuster¹, Stefan Hauser¹, Jakob Admard³², Nicolas Casadei³², Ana Velic³³, Boris Macek³³, Stephan Ossowski³², Henry Houlden³⁴, Reza Maroofian³⁵, Ludger Schöls³⁶

Affiliations

¹ Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany.
² Division of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada.
³ Maritime Medical Genetics Service IWK Health Centre, Halifax, NS B3R 6R8 Canada.
⁴ Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr. Str. 1, 6020 Innsbruck, Austria; Institute of Human Genetics, Technical University of Munich, Trogerstr. 32, 81675 Munich, Germany.
⁵ Department of Pediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Str. 2, 6900 Bregenz, Austria.
⁶ Department of Pathology and Histology, Al-Quds University, Eastern Jerusalem 19356, Palestine.
⁷ Palestine Medical Complex, Ramallah, Palestine.
⁸ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
⁹ Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
¹⁰ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
¹¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Medical Genetics, Cukurova University Faculty of Medicine, 01330 Adana, Turkey.
¹³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
¹⁵ Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁶ Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
¹⁷ Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
¹⁸ Department of Neurology and Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁹ GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
²⁰ Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
²¹ Faculty of Medicine, Al-Quds University, Eastern Jerusalem 19356, Palestine.
²² Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
²³ Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
²⁴ National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
²⁵ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
²⁶ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9WL, UK.
²⁷ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9WL, UK.
²⁸ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
²⁹ Genomics England, London EC1M 6BQ, UK.
³⁰ Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
³¹ Department of Neuroradiology, University Hospital of Tuebingen, 72076 Tübingen, Germany.
³² Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; NGS Competence Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
³³ Proteome Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
³⁴ Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
³⁵ Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK. Electronic address: rmaroofian@gmail.com.
³⁶ Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany. Electronic address: ludger.schoels@uni-tuebingen.de.

Abstract

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.

Keywords: BCAS3; UAS-Gal4; fibroblasts; global developmental delay; microcephaly; neurodevelopmental disorder; proteomics; pyramidal tract involvement; thin corpus callosum; transcriptomics.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Cell Movement
Child
Child, Preschool
Drosophila
Female
Fibroblasts / metabolism
Fibroblasts / pathology
Humans
Infant
Loss of Function Mutation*
Loss of Heterozygosity*
Male
Mice
Mice, Knockout
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Neurodevelopmental Disorders / etiology*
Neurodevelopmental Disorders / metabolism
Neurodevelopmental Disorders / pathology
Pedigree
Proteome / analysis
Young Adult

Substances

BCAS3 protein, human
Neoplasm Proteins
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding